Statins are currently the most therapeutically effective drugs available for reducing low-density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Thus, statins are used in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. A high level of LDL in the bloodstream has been linked to the formation of coronary lesions that obstruct the flow of blood and can rupture and promote thrombosis (Goodman and Gilman, The Pharmacological Basis of Therapeutics, page 879, 9th Ed. 1996).
Statins inhibit cholesterol biosynthesis in humans by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A (“HMG-CoA”) reductase enzyme. HMG-CoA reductase catalyzes the conversion of HMG to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Decreased production of cholesterol causes an increase in the number of LDL receptors and corresponding reduction in the concentration of LDL particles in the bloodstream. Reduction in the LDL level in the bloodstream reduces the risk of coronary artery disease (J.A.M.A. 1984, 251, 351-74).
Currently available statins include lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin and atorvastatin, which are administered in their lactone form, as sodium salts or as calcium salts. Rosuvastatin calcium is disclosed in U.S. Pat. No. 5,260,440.
Rosuvastatin (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid) calcium is an HMG-CoA reductase inhibitor, developed by Shionogi for the once daily oral treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996; Direct communications, Shonogi, 8 Feb. 1999 & 25 Feb. 2000). Rosuvastatin is a superstatin, which can lower LDL-cholesterol and triglycerides levels more effectively than first generation drugs. Rosuvastatin calcium has the following chemical formula:

Rosuvastatin calcium is marketed under the name CRESTOR® for treatment of a mammal such as a human. According to the maker of CRESTOR®, it is administered in a daily dose of from about 5 mg to about 40 mg. For patients requiring less aggressive LDL-C reductions or who have pre-disposing factors for myopathy, the 5 mg dose is recommended, while 10 mg dose is recommended for the average patient, 20 mg dose for patients with marked hyper-cholesterolemia and aggressive lipid targets (>190 mg/dL), and the 40 mg dose for patients who have not been responsive to lower doses. WO 03/032995 further discloses a method of preventing dementia by administering rosuvastatin to a patient.
4-(Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-hydroxymethyl-pyrimidine (FPP-OH) is a key intermediate in the synthesis of rosuvastatin. The oxidation of FPP-OH to 4-(Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine (FPP-CHO) is an important step in the synthesis of rosuvastatin.
EP Patent No. 521,471 and U.S. Pat. No. 5,260,440 disclose the synthesis of rosuvastatin. The oxidation of FPP-OH therein is performed using Tetra Propyl Ammonium Perruthenate (TPAP). Oxidation with TPAP is described in Lenz et al. J. Chem. Soc. PT1, 1997, 3291-3292 and in Ley et al., Synthesis 1994, 639-666. TPAP is an expensive Ruthenium derivative.
There is a need in the art for processes which allow for production of highly pure rosuvastatin in a facile and cost effective manner on an industrial scale.